Degree Name

PhD (Doctor of Philosophy)

Program

Biomedical Sciences

Date of Award

8-2018

Committee Chair or Co-Chairs

Patrick C. Bradshaw

Committee Members

Thomas Jones, Istvan Karsai, Victoria Palau, Antonio Rusinol

Abstract

Investigating similarities among neurological diseases can provide insight into disease processes. Two prominent commonalities of neurological diseases are the formation of amyloid deposits and altered ammonia and glutamate metabolism. Computational techniques were used to explore these processes in several neurological diseases. Residue interaction networks (RINs) abstract protein structure into a series of nodes (representing residues) and edges (representing connections between residues likely to interact). Analyzing the RINs of monomeric forms of amyloidogenic proteins for common network features revealed similarities not previously known. First, amyloidogenic variants of lysozyme were used to demonstrate the usefulness of RINs to the study of amyloidogenic proteins. Next, I compared RINs of amyloidogenic proteins with randomized control networks and a group of real protein controls and found similarities in network structures unique to amyloidogenic proteins. The use of 3D structure data and network structure data of amyloid-beta (1-42) (Abeta42) in a hydrophobic, membrane-mimicking solvent led to the identification of an interaction between Val24 and Ile31 as potentially involved in preventing Abeta aggregation. Since Abeta causes oxidative damage, since the ammonia metabolism enzyme glutamine synthetase is particularly susceptible to oxidative damage, and since glutamate plays a central role in neuronal function, I expanded my research to include the study of ammonia and glutamate metabolism in neurological diseases. A computational model of the effects of the interactions between the amount of dietary protein and the activities of ammonia metabolism enzymes on blood and brain ammonia levels supports potentially important roles for these enzymes in the protection of neural function. Next, I reviewed the role of amino acid catabolism in Alzheimer’s disease (AD). Common tissue pathology and the ability of memantine, an NMDA receptor antagonist, to relieve symptoms in patients and animal models of AD, major depressive disorder (MDD), and type 2 diabetes (T2D) further support a role for ammonia and glutamate metabolism in disease. Lastly, I found that single nucleotide polymorphisms (SNPs) in select ammonia metabolism genes are associated with these three diseases. The results presented in this dissertation demonstrate that investigating neurological diseases using computational approaches can provide great insight into the common underlying pathologies.

Document Type

Dissertation - Withheld

Copyright

Copyright by the authors.

Available for download on Tuesday, July 05, 2022

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